The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity
Mustafa Sibai, Sergi Cervilla, Daniela Grases, Eva Musulén, Rossana Lazcano, Chia-Kuei Mo, Verónica Dávalos, Arola Fortian, Adrià Bernat‐Peguera, Margarita Romeo, Collin Tokheim, Jordi Barretina, Alexander J. Lazar, Li Ding, Enrique Grande, Teresa Alonso-Gordoa, Mario Álvarez-Maestro, Elena Andrada, Ainara Azueta, Raquel Benítez Javier Burgos, Daniel Castellano, M. Angel Climent, Mario Domínguez, Ignacio Durán Albert Font, Isabel Galante, Patricia Galván, Juan F. García, Xavier García del Muro, Félix Guerrero-Ramos, Núria Malats, Miriam Marqués, Pablo Maroto, Jaime Martínez de Villarreal, Ane Moreno-Oya, Jesús M. Paramio, Alvaro Pinto, Aleix Prat, Javier Puente, Oscar Reig, Francisco X. Real, Enrique Grande, Francisco X. Real, Manel Esteller, Matthew H. Bailey, Eduard Porta-Pardo
Abstract
Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we demonstrate interdependent relationships between hallmarks at the junctions of TME and cancer compartments and how they relate to sensitivity to different neoadjuvant treatments in 33 bladder cancer patients from the DUTRENEO trial. In conclusion, our findings may improve our understanding of tumor ecology and help identify new drug biomarkers.