Self-renewal equality in pancreas homeostasis, regeneration, and cancer

Abstract

Two studies by Lodestijn et al. in Cell Stem Cell and Cell Reports reveal a lack of stem cell hierarchies in acinar cell-derived tissue renewal and host instructed clonogenic growth of pancreatic cancer, thereby elucidating determinants of pancreas regeneration and cancer. Two studies by Lodestijn et al. in Cell Stem Cell and Cell Reports reveal a lack of stem cell hierarchies in acinar cell-derived tissue renewal and host instructed clonogenic growth of pancreatic cancer, thereby elucidating determinants of pancreas regeneration and cancer. Main textThe pancreas is central to regulating energy homeostasis. It plays essential roles in digestion of nutrients as well as in control of blood glucose levels. Food digestion is regulated by exocrine glands consisting of acinar cells, which produce and secrete enzymes capable of decomposing nutrients, such as lipids and proteins, thereby enabling their intestinal uptake. Glucose homeostasis is regulated by the islets of Langerhans, which constitute the endocrine pancreas and contain insulin-secreting β cells.Exocrine and endocrine dysfunctions of the pancreas are life-threatening conditions, severely impairing body function. Loss of acinar cells results in malnutrition, while β cell loss leads to diabetes mellitus. Oncogenic transformation of exocrine cells initiates pancreatic ductal adenocarcinoma (PDAC), a disease with poor prognosis. Dissecting the self-renewal and regenerative capacities of pancreatic exocrine and endocrine cell lineages is therefore critical for a better understanding of human health and disease.For decades, the hematopoietic system has been the prime example of stem-cell-driven tissue renewal hierarchies and oncogenesis. In recent years, it has been shown that other adult tissue types follow a stem-cell-driven hierarchy, including the epithelium of the intestine and the epidermis. The pancreas has been considered a dormant organ for many years. However, recent studies demonstrate that the adult exocrine and endocrine pancreas display considerable self-renewing capacities (Gribben et al., 2021Gribben C. Lambert C. Messal H.A. Hubber E.L. Rackham C. Evans I. Heimberg H. Jones P. Sancho R. Behrens A. Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.Cell Stem Cell. 2021; 28: 2000-2008.e4Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar; Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar; Murtaugh and Keefe, 2015Murtaugh L.C. Keefe M.D. Regeneration and repair of the exocrine pancreas.Annu. Rev. Physiol. 2015; 77: 229-249Crossref PubMed Scopus (115) Google Scholar), and, surprisingly, no classical stem cells hierarchies have been identified to be capable of regenerating all pancreatic lineages. In PDAC, specific cancer stem cell subpopulations have been proposed to drive the disease, mediating both tumor progression and metastatic dissemination (Hermann et al., 2007Hermann P.C. Huber S.L. Herrler T. Aicher A. Ellwart J.W. Guba M. Bruns C.J. Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.Cell Stem Cell. 2007; 1: 313-323Abstract Full Text Full Text PDF PubMed Scopus (2247) Google Scholar). This concept has been challenged by recent studies showing remarkable plasticity of tumor cells but no classical stem cell hierarchy in this cancer type (Ball et al., 2017Ball C.R. Oppel F. Ehrenberg K.R. Dubash T.D. Dieter S.M. Hoffmann C.M. Abel U. Herbst F. Koch M. Werner J. et al.Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts.EMBO Mol. Med. 2017; 9: 918-932Crossref PubMed Scopus (26) Google Scholar).Accordingly, and in contrast to the classical hierarchic stem cell concept, pancreas regeneration upon injury (i.e., acute pancreatitis) is driven, at least partially, by remarkable plasticity of differentiated acinar cells that are able to revert back to an immature, progenitor-like state (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Interestingly, this plasticity depends on the embryonic hedgehog pathway, which is also crucial for PDAC formation (Roy and Hebrok, 2015Roy N. Hebrok M. Regulation of Cellular Identity in Cancer.Dev. Cell. 2015; 35: 674-684Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar).Acinar cells display considerable heterogeneity. So far, it is unclear which sub-cell type of the acinar compartment is the cell of origin of self-renewal. To understand the principles of tissue maintenance and regeneration in the adult pancreas, Lodestijn et al., 2021aLodestijn S.C. van den Bosch T. Nijman L.E. Moreno L.F. Schlingemann S. Sheraton V.M. van Neerven S.M. Koning J.J. Vieira Braga F.A. Paauw N.J. et al.Continuous clonal labeling reveals uniform progenitor potential in the adult exocrine pancreas.Cell Stem Cell. 2021; 28: 2009-2019.e4Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar combined elegant marker-agnostic in vivo lineage-tracing experiments with advanced computational modeling methods. They employed a sophisticated proliferation-dependent reporter system relying on an out-of-frame fluorescent protein, which can be stochastically activated during replication following strand slippage of a dinucleotide repeat. Using this approach, they show that the adult exocrine pancreas lacks a hierarchic tissue architecture. All differentiated acinar cells are capable of self-renewal by self-replication, breaking the dogma that only specialized, rare cell subpopulations act as progenitors. Interestingly, pancreatic regeneration is driven by two distinct routes: the intra-acinar replacement of cells and acinar gland duplications through acinar fission-like events (Figure 1). By establishing a quantitative model of acinar cell renewal, the study provides important insights into the cellular dynamics that regulate tissue homeostasis and the regenerative capacity of the exocrine pancreas with possible implications for regenerative medicine in the future.In pancreatic cancer, the presence and role of cellular hierarchies is controversial, and the mechanisms that drive clonal dynamics of cancer cells are still enigmatic. In their recent Cell Reports paper, Lodestijn and colleagues addressed this important question with a second advanced stochastic clonal labeling system combined with quantitative mathematical modeling and investigated the growth dynamics of PDAC cells in vivo (Lodestijn et al., 2021bLodestijn S.C. Miedema D.M. Lenos K.J. Nijman L.E. Belt S.C. El Makrini K. Lecca M.C. Waasdorp C. van den Bosch T. Bijlsma M.F. Vermeulen L. Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.Cell Rep. 2021; 37: 109852Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). They show that all cells of this highly aggressive and lethal tumor type are capable of tumor initiation and self-renewal, excluding a cancer cell intrinsic hierarchical stem cell architecture. Contrary to other tumor types, they demonstrate that the clonogenic capacity of PDAC cells is driven by tumor microenvironmental (TME) cues. Notably, activated cancer-associated fibroblasts (CAFs) with a myofibroblast-like phenotype (myoCAFs) and their proximity and communication to tumor cells define the clonogenic activity and expansion of PDAC cells in vivo (Figure 1). In line with this finding, targeting activated CAFs via blockade of hedgehog signaling, which is also important for acinar self-renewal (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), alters the clonal dynamics, but not the growth of pancreatic tumors. By demonstrating that distinct host cells instruct the clonogenic hierarchy of PDAC cells in vivo, this study will emerge as a landmark for future research.CAFs are a heterogeneous spatially confined population with diverse and often opposing features. Their impact on PDAC development and progression might depend on the CAF subtype and the proximity to cancer cells. Whereas inflammatory CAFs (iCAFs) are located more distantly to tumor cells, myoCAFs expressing high levels of α-SMA and low levels of inflammatory mediators reside in close proximity to PDAC cells (Öhlund et al., 2017Öhlund D. Handly-Santana A. Biffi G. Elyada E. Almeida A.S. Ponz-Sarvise M. Corbo V. Oni T.E. Hearn S.A. Lee E.J. et al.Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.J. Exp. Med. 2017; 214: 579-596Crossref PubMed Scopus (987) Google Scholar). In the future, it will be crucial to understand how CAF with PDAC cells in This will be essential for the of cell communication and in and of PDAC such as the highly of host cell subpopulations in vivo et al., N. K. C. C. M. S. M.C. P. et system for and targeting of pancreatic Med. PubMed Scopus (151) Google Scholar), will for such with the sophisticated quantitative by Lodestijn and a understanding of the that the has an important role in tumor and to The of Lodestijn and colleagues for the targeting of Main textThe pancreas is central to regulating energy homeostasis. It plays essential roles in digestion of nutrients as well as in control of blood glucose levels. Food digestion is regulated by exocrine glands consisting of acinar cells, which produce and secrete enzymes capable of decomposing nutrients, such as lipids and proteins, thereby enabling their intestinal uptake. Glucose homeostasis is regulated by the islets of Langerhans, which constitute the endocrine pancreas and contain insulin-secreting β cells.Exocrine and endocrine dysfunctions of the pancreas are life-threatening conditions, severely impairing body function. Loss of acinar cells results in malnutrition, while β cell loss leads to diabetes mellitus. Oncogenic transformation of exocrine cells initiates pancreatic ductal adenocarcinoma (PDAC), a disease with poor prognosis. Dissecting the self-renewal and regenerative capacities of pancreatic exocrine and endocrine cell lineages is therefore critical for a better understanding of human health and disease.For decades, the hematopoietic system has been the prime example of stem-cell-driven tissue renewal hierarchies and oncogenesis. In recent years, it has been shown that other adult tissue types follow a stem-cell-driven hierarchy, including the epithelium of the intestine and the epidermis. The pancreas has been considered a dormant organ for many years. However, recent studies demonstrate that the adult exocrine and endocrine pancreas display considerable self-renewing capacities (Gribben et al., 2021Gribben C. Lambert C. Messal H.A. Hubber E.L. Rackham C. Evans I. Heimberg H. Jones P. Sancho R. Behrens A. Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.Cell Stem Cell. 2021; 28: 2000-2008.e4Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar; Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar; Murtaugh and Keefe, 2015Murtaugh L.C. Keefe M.D. Regeneration and repair of the exocrine pancreas.Annu. Rev. Physiol. 2015; 77: 229-249Crossref PubMed Scopus (115) Google Scholar), and, surprisingly, no classical stem cells hierarchies have been identified to be capable of regenerating all pancreatic lineages. In PDAC, specific cancer stem cell subpopulations have been proposed to drive the disease, mediating both tumor progression and metastatic dissemination (Hermann et al., 2007Hermann P.C. Huber S.L. Herrler T. Aicher A. Ellwart J.W. Guba M. Bruns C.J. Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.Cell Stem Cell. 2007; 1: 313-323Abstract Full Text Full Text PDF PubMed Scopus (2247) Google Scholar). This concept has been challenged by recent studies showing remarkable plasticity of tumor cells but no classical stem cell hierarchy in this cancer type (Ball et al., 2017Ball C.R. Oppel F. Ehrenberg K.R. Dubash T.D. Dieter S.M. Hoffmann C.M. Abel U. Herbst F. Koch M. Werner J. et al.Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts.EMBO Mol. Med. 2017; 9: 918-932Crossref PubMed Scopus (26) Google Scholar).Accordingly, and in contrast to the classical hierarchic stem cell concept, pancreas regeneration upon injury (i.e., acute pancreatitis) is driven, at least partially, by remarkable plasticity of differentiated acinar cells that are able to revert back to an immature, progenitor-like state (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Interestingly, this plasticity depends on the embryonic hedgehog pathway, which is also crucial for PDAC formation (Roy and Hebrok, 2015Roy N. Hebrok M. Regulation of Cellular Identity in Cancer.Dev. Cell. 2015; 35: 674-684Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar).Acinar cells display considerable heterogeneity. So far, it is unclear which sub-cell type of the acinar compartment is the cell of origin of self-renewal. To understand the principles of tissue maintenance and regeneration in the adult pancreas, Lodestijn et al., 2021aLodestijn S.C. van den Bosch T. Nijman L.E. Moreno L.F. Schlingemann S. Sheraton V.M. van Neerven S.M. Koning J.J. Vieira Braga F.A. Paauw N.J. et al.Continuous clonal labeling reveals uniform progenitor potential in the adult exocrine pancreas.Cell Stem Cell. 2021; 28: 2009-2019.e4Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar combined elegant marker-agnostic in vivo lineage-tracing experiments with advanced computational modeling methods. They employed a sophisticated proliferation-dependent reporter system relying on an out-of-frame fluorescent protein, which can be stochastically activated during replication following strand slippage of a dinucleotide repeat. Using this approach, they show that the adult exocrine pancreas lacks a hierarchic tissue architecture. All differentiated acinar cells are capable of self-renewal by self-replication, breaking the dogma that only specialized, rare cell subpopulations act as progenitors. Interestingly, pancreatic regeneration is driven by two distinct routes: the intra-acinar replacement of cells and acinar gland duplications through acinar fission-like events (Figure 1). By establishing a quantitative model of acinar cell renewal, the study provides important insights into the cellular dynamics that regulate tissue homeostasis and the regenerative capacity of the exocrine pancreas with possible implications for regenerative medicine in the future.In pancreatic cancer, the presence and role of cellular hierarchies is controversial, and the mechanisms that drive clonal dynamics of cancer cells are still enigmatic. In their recent Cell Reports paper, Lodestijn and colleagues addressed this important question with a second advanced stochastic clonal labeling system combined with quantitative mathematical modeling and investigated the growth dynamics of PDAC cells in vivo (Lodestijn et al., 2021bLodestijn S.C. Miedema D.M. Lenos K.J. Nijman L.E. Belt S.C. El Makrini K. Lecca M.C. Waasdorp C. van den Bosch T. Bijlsma M.F. Vermeulen L. Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.Cell Rep. 2021; 37: 109852Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). They show that all cells of this highly aggressive and lethal tumor type are capable of tumor initiation and self-renewal, excluding a cancer cell intrinsic hierarchical stem cell architecture. Contrary to other tumor types, they demonstrate that the clonogenic capacity of PDAC cells is driven by tumor microenvironmental (TME) cues. Notably, activated cancer-associated fibroblasts (CAFs) with a myofibroblast-like phenotype (myoCAFs) and their proximity and communication to tumor cells define the clonogenic activity and expansion of PDAC cells in vivo (Figure 1). In line with this finding, targeting activated CAFs via blockade of hedgehog signaling, which is also important for acinar self-renewal (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), alters the clonal dynamics, but not the growth of pancreatic tumors. By demonstrating that distinct host cells instruct the clonogenic hierarchy of PDAC cells in vivo, this study will emerge as a landmark for future research.CAFs are a heterogeneous spatially confined population with diverse and often opposing features. Their impact on PDAC development and progression might depend on the CAF subtype and the proximity to cancer cells. Whereas inflammatory CAFs (iCAFs) are located more distantly to tumor cells, myoCAFs expressing high levels of α-SMA and low levels of inflammatory mediators reside in close proximity to PDAC cells (Öhlund et al., 2017Öhlund D. Handly-Santana A. Biffi G. Elyada E. Almeida A.S. Ponz-Sarvise M. Corbo V. Oni T.E. Hearn S.A. Lee E.J. et al.Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.J. Exp. Med. 2017; 214: 579-596Crossref PubMed Scopus (987) Google Scholar). In the future, it will be crucial to understand how CAF with PDAC cells in This will be essential for the of cell communication and in and of PDAC such as the highly of host cell subpopulations in vivo et al., N. K. C. C. M. S. M.C. P. et system for and targeting of pancreatic Med. PubMed Scopus (151) Google Scholar), will for such with the sophisticated quantitative by Lodestijn and a understanding of the that the has an important role in tumor and to The of Lodestijn and colleagues for the targeting of The pancreas is central to regulating energy homeostasis. It plays essential roles in digestion of nutrients as well as in control of blood glucose levels. Food digestion is regulated by exocrine glands consisting of acinar cells, which produce and secrete enzymes capable of decomposing nutrients, such as lipids and proteins, thereby enabling their intestinal uptake. Glucose homeostasis is regulated by the islets of Langerhans, which constitute the endocrine pancreas and contain insulin-secreting β cells. and endocrine dysfunctions of the pancreas are life-threatening conditions, severely impairing body function. Loss of acinar cells results in malnutrition, while β cell loss leads to diabetes mellitus. Oncogenic transformation of exocrine cells initiates pancreatic ductal adenocarcinoma (PDAC), a disease with poor prognosis. Dissecting the self-renewal and regenerative capacities of pancreatic exocrine and endocrine cell lineages is therefore critical for a better understanding of human health and decades, the hematopoietic system has been the prime example of stem-cell-driven tissue renewal hierarchies and oncogenesis. In recent years, it has been shown that other adult tissue types follow a stem-cell-driven hierarchy, including the epithelium of the intestine and the epidermis. The pancreas has been considered a dormant organ for many years. However, recent studies demonstrate that the adult exocrine and endocrine pancreas display considerable self-renewing capacities (Gribben et al., 2021Gribben C. Lambert C. Messal H.A. Hubber E.L. Rackham C. Evans I. Heimberg H. Jones P. Sancho R. Behrens A. Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.Cell Stem Cell. 2021; 28: 2000-2008.e4Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar; Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar; Murtaugh and Keefe, 2015Murtaugh L.C. Keefe M.D. Regeneration and repair of the exocrine pancreas.Annu. Rev. Physiol. 2015; 77: 229-249Crossref PubMed Scopus (115) Google Scholar), and, surprisingly, no classical stem cells hierarchies have been identified to be capable of regenerating all pancreatic lineages. In PDAC, specific cancer stem cell subpopulations have been proposed to drive the disease, mediating both tumor progression and metastatic dissemination (Hermann et al., 2007Hermann P.C. Huber S.L. Herrler T. Aicher A. Ellwart J.W. Guba M. Bruns C.J. Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer.Cell Stem Cell. 2007; 1: 313-323Abstract Full Text Full Text PDF PubMed Scopus (2247) Google Scholar). This concept has been challenged by recent studies showing remarkable plasticity of tumor cells but no classical stem cell hierarchy in this cancer type (Ball et al., 2017Ball C.R. Oppel F. Ehrenberg K.R. Dubash T.D. Dieter S.M. Hoffmann C.M. Abel U. Herbst F. Koch M. Werner J. et al.Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts.EMBO Mol. Med. 2017; 9: 918-932Crossref PubMed Scopus (26) Google Scholar). and in contrast to the classical hierarchic stem cell concept, pancreas regeneration upon injury (i.e., acute pancreatitis) is driven, at least partially, by remarkable plasticity of differentiated acinar cells that are able to revert back to an immature, progenitor-like state (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Interestingly, this plasticity depends on the embryonic hedgehog pathway, which is also crucial for PDAC formation (Roy and Hebrok, 2015Roy N. Hebrok M. Regulation of Cellular Identity in Cancer.Dev. Cell. 2015; 35: 674-684Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). cells display considerable heterogeneity. So far, it is unclear which sub-cell type of the acinar compartment is the cell of origin of self-renewal. To understand the principles of tissue maintenance and regeneration in the adult pancreas, Lodestijn et al., 2021aLodestijn S.C. van den Bosch T. Nijman L.E. Moreno L.F. Schlingemann S. Sheraton V.M. van Neerven S.M. Koning J.J. Vieira Braga F.A. Paauw N.J. et al.Continuous clonal labeling reveals uniform progenitor potential in the adult exocrine pancreas.Cell Stem Cell. 2021; 28: 2009-2019.e4Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar combined elegant marker-agnostic in vivo lineage-tracing experiments with advanced computational modeling methods. They employed a sophisticated proliferation-dependent reporter system relying on an out-of-frame fluorescent protein, which can be stochastically activated during replication following strand slippage of a dinucleotide repeat. Using this approach, they show that the adult exocrine pancreas lacks a hierarchic tissue architecture. All differentiated acinar cells are capable of self-renewal by self-replication, breaking the dogma that only specialized, rare cell subpopulations act as progenitors. Interestingly, pancreatic regeneration is driven by two distinct routes: the intra-acinar replacement of cells and acinar gland duplications through acinar fission-like events (Figure 1). By establishing a quantitative model of acinar cell renewal, the study provides important insights into the cellular dynamics that regulate tissue homeostasis and the regenerative capacity of the exocrine pancreas with possible implications for regenerative medicine in the In pancreatic cancer, the presence and role of cellular hierarchies is controversial, and the mechanisms that drive clonal dynamics of cancer cells are still enigmatic. In their recent Cell Reports paper, Lodestijn and colleagues addressed this important question with a second advanced stochastic clonal labeling system combined with quantitative mathematical modeling and investigated the growth dynamics of PDAC cells in vivo (Lodestijn et al., 2021bLodestijn S.C. Miedema D.M. Lenos K.J. Nijman L.E. Belt S.C. El Makrini K. Lecca M.C. Waasdorp C. van den Bosch T. Bijlsma M.F. Vermeulen L. Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic cancer.Cell Rep. 2021; 37: 109852Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). They show that all cells of this highly aggressive and lethal tumor type are capable of tumor initiation and self-renewal, excluding a cancer cell intrinsic hierarchical stem cell architecture. Contrary to other tumor types, they demonstrate that the clonogenic capacity of PDAC cells is driven by tumor microenvironmental (TME) cues. Notably, activated cancer-associated fibroblasts (CAFs) with a myofibroblast-like phenotype (myoCAFs) and their proximity and communication to tumor cells define the clonogenic activity and expansion of PDAC cells in vivo (Figure 1). In line with this finding, targeting activated CAFs via blockade of hedgehog signaling, which is also important for acinar self-renewal (Fendrich et al., 2008Fendrich V. Esni F. Garay M.V. Feldmann G. Habbe N. Jensen J.N. Dor Y. Stoffers D. Jensen J. Leach S.D. Maitra A. Hedgehog signaling is required for effective regeneration of exocrine pancreas.Gastroenterology. 2008; 135: 621-631Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), alters the clonal dynamics, but not the growth of pancreatic tumors. By demonstrating that distinct host cells instruct the clonogenic hierarchy of PDAC cells in vivo, this study will emerge as a landmark for future CAFs are a heterogeneous spatially confined population with diverse and often opposing features. Their impact on PDAC development and progression might depend on the CAF subtype and the proximity to cancer cells. Whereas inflammatory CAFs (iCAFs) are located more distantly to tumor cells, myoCAFs expressing high levels of α-SMA and low levels of inflammatory mediators reside in close proximity to PDAC cells (Öhlund et al., 2017Öhlund D. Handly-Santana A. Biffi G. Elyada E. Almeida A.S. Ponz-Sarvise M. Corbo V. Oni T.E. Hearn S.A. Lee E.J. et al.Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.J. Exp. Med. 2017; 214: 579-596Crossref PubMed Scopus (987) Google Scholar). In the future, it will be crucial to understand how CAF with PDAC cells in This will be essential for the of cell communication and in and of PDAC such as the highly of host cell subpopulations in vivo et al., N. K. C. C. M. S. M.C. P. et system for and targeting of pancreatic Med. PubMed Scopus (151) Google Scholar), will for such with the sophisticated quantitative by Lodestijn and a understanding of the that the has an important role in tumor and to The of Lodestijn and colleagues for the targeting of Marker-free lineage tracing reveals an environment-instructed clonogenic hierarchy in pancreatic et et al. lineage tracing in pancreatic cancer to demonstrate that clonogenic capacity of tumor cells is by the and not by features. targeting the Hedgehog alters clonal dynamics but not tumor PDF clonal labeling reveals uniform progenitor potential in the adult exocrine et Stem dynamics of tissue maintenance in the adult exocrine pancreas are In this Lodestijn et al. a of and computational to reveal that is no hierarchy in the adult exocrine pancreas and that all cells can act as progenitors. PDF

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