title: Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers.
abstract: Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development.
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.|Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Mandar Deepak
authors: MD
authors: Muzumdar
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.
authors: Kimberly Judith
authors: KJ
authors: Dorans
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.
authors: Katherine Minjee
authors: KM
authors: Chung
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.
authors: Rebecca
authors: R
authors: Robbins
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.
authors: Tuomas
authors: T
authors: Tammela
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.
authors: Vasilena
authors: V
authors: Gocheva
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Carman Man-Chung
authors: CM
authors: Li
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue 75-453, Cambridge, Massachusetts 02139, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Tyler
authors: T
authors: Jacks
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)