In the first presentation of the session, Dr. Danny Welch (University of Kansas Medical Center) provided an overview of the molecular biology driving metastasis, highlighting key steps of the metastatic cascade. Dr. Welch explained that four distinct types of tumour cell migration have been characterized and also highlighted the ability of these cells to alter their behavior, a phenomenon known as cellular plasticity.
Dr. Welch then went on to describe the 3 different types of genes involved in the regulation of metastasis: 1) pro-metastatic genes which drive tumour spread; 2) metastasis suppressors which are defined by their ability to block metastasis without preventing primary tumour growth, and 3) metastasis modifiers. Dr.Welch subsequently explained that the existence of metastasis suppressor genes provides genetic proof that metastases are a distinct phenotype.
His take-home messages were:
- Tumorigenicity and metastasis are distinct phenotypes
- Primary tumours and metastasis cannot (and should not) be treated equivalently
In the next talk, Dr. Michael Henry (University of Iowa Health Care) discussed the biomechanics of circulating tumour cells (CTCs). He began by describing the journey of CTCs into the vasculature, emphasizing that the vast majority of CTCs entering the circulation do not produce clinically evident metastases. Dr. Henry explained that CTCs only exist freely in the circulation for brief periods of time, spending much longer entrapped in the microcirculation of various organs. During this time, CTCs are exposed to a number of different forces including fluid shear stress (FSS), traction, and compression. Although these forces were previously thought to be mechanically destructive to CTCs, emerging data provides evidence to the contrary. Dr. Henry highlighted work from his lab, which found that resistance to FSS is a biophysical property of malignant cells.2 Additionally FSS exposure was found to make cancer cells ‘stiffer’.3 Furthermore, viable CTCs have been found to actively resist destruction in the circulation by hemodynamic forces through a mechano-adaptive mechanism involving the RhoA-myosin II axis.4 Dr. Henry concluded his talk by considering the potential role of FSS resistance as a biomarker that might be exploited for diagnostic or therapeutic applications in bladder and other cancers.
In the third talk of the session, Dr. William Kim (UNC-Chapel Hill) provided clinical perspectives, highlighting work from his own lab in addition to discussing studies demonstrating that luminal and basal-squamous subtypes may have different subtype stability in lymph node (LN) metastases,5 and that LN and distant metastases undergo clonal evolution.6,7
In the penultimate talk, Dr. Ben Woolbright (University of Kansas Medical Center) discussed the possible contributions of mitochondrial polymorphisms to bladder cancer development and metastasis. He began by discussing the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model and its utility for studying metastasis. The model has been shown to produces tumours that are similar to human MIBC. Dr. Welch concluded that although the BBN model may not well suited to finding negative regulators of metastasis, it may be an acceptable model for identifying positive regulators of metastasis.
The next part of his talk focused on mitochondrial DNA (mtDNA). The mitochondrial genome is maternally derived and encodes genes involved in oxidative phosphorylation. His summary points were:
- mtDNA can serve as a regulator for cancer progression and metastasis and this is likely due to alterations in mitochondria ROS and subsequent cellular signaling changes in diverse pathways.
- mtDNA is depleted in human bladder cancer although the implications of this are currently unclear.
- The MNX model provides a potential means for evaluating the contribution of mtDNA to progression and metastases.
- The potential to define SNPs and/or deletions associated with alterations in mtDNA function may ultimately lead to biomarkers associated with BCa incidence/progression/metastasis.
Dr. Welch gave the last talk of the morning session where he discussed the impact of stromal mitochondrial polymorphisms on cancer metastasis. He concluded by suggesting mtDNA SNP may partially explain racial and sex differences observed in bladder cancer.
Presented by: Danny Welch, PhD, University of Kansas Medical Center; Michael Henry, PhD, University of Iowa Health Care; William Kim, MD, UNC-Chapel Hill; Ben Woolbright, PhD, University of Kansas Medical Center
Written by: Niyati Lobo, MD, The Urology Foundation Fulbright Scholar, Twitter: @niyatilobo, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh at the 7th Annual Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium, Sept 16, 2021- Sep 18, 2021.
References:
- Welch DR & Hurst DR. Defining the hallmarks of metastasis. Cancer Res 2019; 79: 3011-2027
- Matthew Barnes J, Nauseef JT, Henry MD. Resistance to fluid shear stress is a conservedbiophysical property of malignant cells. PLOS One 2012; 7: e50973
- Chivukula VK, Krog BL, Nauseef JT et al. Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study. Cell Health Cytoskelet 2015; 7: 25-35.
- Moose DL, Krog BL, Kim TH et al. Cancer cells resist mechanical destruction in circulation via RhoA/Actomyosin-dependent mechano-adaptation. Cell Reports 2020; 30: 3864-3874
- Sjödahl G, Eriksson P, Lövgren K et al. Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases. Mod Pathol 2018; 31: 1869-1881
- Thomsen MBH, Nordentoft I, Lamy P. Spatial and temporal clonal evolution during development of metastatic urothelial carcinoma. Mol Oncol 2016; 10: 1450-1460
- Faltas BM, Prandi D, Tagawa ST. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nature Genetics 2016; 48: 1490-1499