Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression

Abstract

Cancer evolution determines molecular and morphological intra-tumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histological features remains elusive. Here, we generated multi-omics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intra-tumor spatial heterogeneity, tracing non-genetic routes of cancer evolution. Statement of significance Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized non-genetic mechanisms underlying intra-tumor patterns and molecular markers predicting patient prognosis. Intra-tumor patterns determined diverse immune microenvironments warranting their study in the context of current immunotherapies.

Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx® Digital Spatial Profiler

“…With these key advantages, GeoMx allows researchers to achieve a wide spectrum of spatially resolved transcriptomic and proteomic characterizations of breast cancer samples [4,35,[45][46][47]. Furthermore, the GeoMx spatial profiling is applicable for other tumor types, such as melanoma, lung, prostate, or liver cancers, characterized by high clinical and histological heterogeneity [48][49][50][51][52][53][54][55][56][57][58][59][60].…”

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

“…LUAD progression is driven by epigenetic changes that lead to increased plasticity relative to normal cells of origin, which ultimately enables cancer cells to undergo profound changes in cell identity that enhance malignant potential [1][2][3][5][6][7][8][9][10][11][12] . Here we show that FoxA1/2 regulate critical aspects of lineage plasticity and infidelity, coordinately driving multiple cell identity programs that are essential for LUAD progression (Figure 7H, top).…”

The many faces of cancer evolution

“…In lung adenocarcinomas, the tumor tissue architecture is often heterogeneous, especially in early-stage diseases, and it gives rise to histologic patterns recognized by histopathology analyses (Travis et al, 2015). Recent evidence from histopathology-guided multiregional sampling has ll OPEN ACCESS iScience 24, 102403, May 21, 2021 shown that this heterogeneity does not correspond to emergence of specific genetic variants, but it rather reflects epigenetic and transcriptional reprogramming associated with cell de-differentiation and increased proliferation (Tavernari et al, 2021). Additional examples include reprogramming to a progenitor state of luminal breast cancer cells (Domenici et al, 2019;Poli et al, 2018), intermixing and transition between differentiated and progenitor states in melanoma (Cheli et al, 2011;Roesch et al, 2010), epithelial plasticity in pancreatic cancer (Genovese et al, 2017;Reichert et al, 2018), de-differentiation trajectories in glioblastoma (Gallo et al, 2015), or lineage reprogramming from adeno to neuroendocrine carcinoma in prostate and lung cancer (Park et al, 2018), which, similarly to EMT, shows evidence of a continuum of states along which individual tumors may transition and evolve (Ireland et al, 2020).…”