Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Haoyu Wang, Tivadar Török, Juliano Ribeiro, Jessie Xue, Erik C Cardoso, Yao Rong, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Edridge D'Souza, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Min Dai, Giovanni Marrero, Vipin Kumar, Anjali Saqi, Benjamin Herzberg, Benjamin Izar, Howard Y Chang, Joo-Hyeon Lee, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang
ASAP2 represents a CAIS-associated exploratory candidate with preliminary peripheral detectability. These findings support further investigation of downstream molecular networks after AR deficiency and possible androgen-pathway disruption. They do not establish ASAP2 as a clinical diagnostic biomarker. Larger multicenter cohorts, relevant 46,XY DSD comparators, and functional studies are required to clarify whether ASAP2 can serve as a surrogate readout of broader androgen-pathway disruption.
Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Here we integrate high-resolution spatial transcriptomics and evolving lineage-tracing technologies to elucidate how tumor expansion, plasticity and metastasis co-evolve with microenvironmental remodeling in a Kras;Trp53-driven mouse model of lung adenocarcinoma. We find that subclonal expansion contributes to a hypoxic, immunosuppressive and fibrotic microenvironment that is associated with the emergence of prometastatic cancer cell states. We use tumor phylogeography to delineate intercellular interactions that are rewired in the expanding tumor niche and use co-culture systems to dissect how intercellular interactions and hypoxia influence cancer cell state. Furthermore, we find that metastases arise from spatially confined primary tumor subclones and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.