Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer

Abstract

Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.

Keywords: adaptive responses; breast cancer; intra-tumor heterogeneity; metastatic cascade; mutational profile.

Figure 1

The BC Metastatic Progression is a Multistep Process. The metastatic process implies local invasion of the PT by cancer cells, followed by intravasation in the tumor vasculature. Once arrested in the capillary bed, cells enter the circulatory system. Cancer cells in the circulation are vulnerable to the attacks of the immune system, particularly exerted by Natural Killer cells, which proceed to tumor cell rapid clearance. Immune resistant cancer cells move along the blood vessels as single cells or clusters coated with platelets, and disseminate to secondary sites, passively following the circulatory patterns. Upon their arrival in the capillaries of a distant organ, cancer cells extravasate and start to colonize the foreign parenchyma. Colonization comprises many steps that occur in a timescale of years, during which time cells develop resistance to immunity, adapt to the novel microenvironment and settle in a pre-metastatic niche which support their survival and tumor-initiating capacity. At the metastatic site, cancer cells may be either eliminated or enter in a quiescent state as single cells or micro-metastases. Once the cancer cells break out of dormancy, they reinitiate outgrowth to form an overt metastasis in the distant organ microenvironment (figure created with BioRender.com (accessed on 26 March 2022)).

Figure 2

Adaptive Responses in BC Metastatization. During tumor progression, cancer cells encounter different kinds of microenvironmental stressors, such as hypoxia, nutrient deprivation, ER stress and physical obstacles while in transit, besides being exposed to therapeutic drugs. To increase stress tolerance and survive in a hostile environment, cells activate adaptive stress response pathways. These phenotypic adaptations are regulated in a spatial and temporal manner and foster intratumor heterogeneity, thereby endowing a subset of cancer cells with metastatic traits. Adaptive stress responses in the PT lead to EMT, immune escape, metabolic reprogramming and, through active remodeling of ECM and neo-angiogenesis events, enable cells to leave the PT site. Stress signaling also increases the capacity of cancer cells to survive in the circulation and extravasate, eluding immune surveillance and chemotherapy-induced apoptosis. Adaptive pathways at metastatic site regulate the growth dynamics of disseminated cells: once arrested in the target organ, cells can either enter dormancy to tolerate the foreign environment or reinitiate tumor growth (figure created with BioRender.com (accessed on 26 March 2022)).