kshitizlab

Evolution of Stromal Resistance

Certain mammals do not suffer from malignancy of epithelia derived cancers. Curiously, these mammals also have a very different “non invasive” placentation during pregnancy. Together with Gunter Wagner, we have established the ELI (Evolved Levels of Invasibility) hypothesis. ELI posits that evolution of non-invasive placentation is a stromal innovation achieved by increased stromal resistance to invasion. 
Based on ELI, we have used comparative placental invasion as a “physiologically normal model” to test the stromal response to cancer/placental invasion. 

Key Findings

  • Cows exhibit very low cancer malignancy vs humans. We have shown that this effect is a “stromal” phenomenon. Cow stroma has evolved to become highly resistant to invasion to prevent placental invasion during pregnancy. A secondary effect is that the stroma also prevents cancer metastasis.  (Kshitiz et al., Nature EE, 2019)
  • Genes that have changed with the evolution of non-invasive placentation have a significant bearing on human cancers. The evolved stromal changes in the endometrium can inform us about stromal control of human carcinomas, particularly melanoma, and pancreatic ductal adenocarcinoma. (Suhail Y et al., PNAS, 2022; Liu S et al., Cancers, 2022).

Relevant Publications 

  1. Dighe A, Maziarz J, Ibrahim-Hasin A, Gatenby RA, Kshitiz, Levchenko A, Wagner GP (2024), Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts, iScience 27(1), 108593.
  2. Liu S, Suhail Y, Novin A, Perpetua L, Kshitiz (2022). Metastatic Transition of Pancreatic Ductal Cell Adenocarcinoma is Accompanied by the Emergence of Pro-Invasive Cancer-Associated Fibroblasts, Cancers, 14(9), 2197.
  3. Suhail Y, Maziarz J.D., Novin A, Dighe A, Afzal J, Wagner G, Kshitiz (2022). Tracing the cis-regulatory changes underlying the endometrial control of placental invasion, Proceedings of the National Academy of Sciences, 119(6).
  4. Wagner GP±, Kshitiz, Dighe A, Levchenko A (2021). The Coevolution of Placentation and Cancer, Annual Review of Animal Biosciences, 10, 259-279.
  5. Suhail Y, Afzal J, Kshitiz (2021). Evolved Resistance to Placental Invasion Secondarily Confers Increased Survival in Melanoma Patients, Journal of Clinical Medicine, 10(595).
  6. Novin A, Suhail Y, Ajeti V, Goyal R, Wali K, Seck A, Jackson A, Kshitiz (2021). Diversity in cancer invasion phenotypes indicates specific stroma regulated programs, Human Cell, 34(1), 111-121.
  7. Wagner G, Kshitiz, Levchenko A (2020). Comments on Boddy et al., 2020: Available data suggests positive relationship between placental invasion and malignancy, Evolution, Medicine, & Public Health, 1, 211-214.
  8. Kshitiz±, Afzal J, Maziarz JD, Hamidzadeh A, Liang C, Erkenbrack EM, Ham H, Haeger, JD, Pfarrer C, Hoang T, Ott T, Spencer T, Pavlicev M, Antczak D, Levchenko A±, Wagner GP± (2019). The Evolution of Placental Invasion and Cancer Metastasis are Causally Linked, Nature Ecology and Evolution (Accepted). ±: Corresponding Authors