【STTT】Tongji University Fang Jianmin et al. discovered a new cell membrane marker for cancer stem cells, targeting it with therapeutic potential!

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Written by Mia

Cancer stem cells (CSCs) are thought to be responsible for cancer initiation, growth, recurrence, metastasis, and drug
resistance.
Therefore, targeted CSCs are an effective cancer treatment
.
However, few CSC-specific targets with functional extracellular domains have been used to develop antibody drugs
.

Recently, the team of Professor Fang Jianmin and Professor Qin Huanlong and Professor Gao Hua of Tongji University jointly published a research paper
entitled "Targeting TM4SF1 exhibits therapeutic potential via inhibition of cancer stem cells" at Signal Transduction and Targeted Therapy 。 The study confirmed that transmembrane 4 L six family member 1 (TM4SF1) is a cell membrane marker for CSCs, and monoclonal antibodies (mAbs) targeting the functional extracellular domain of TM4SF1 can inhibit CSCs
.

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 01 

The researchers' previously published paper showed that TM4SF1-coupled discoidin domain receptor tyrosine kinase 1 (DDR1) activated JAK2-STAT3 signaling
when stimulated by type I collagen.
This atypical DDR1 signaling maintains the performance of CSC signatures by inducing the expression of SOX2 and NANOG and drives multi-organ metastasis
.

Overview of the study

 02 

Immunohistochemical staining of 16 tumors and adjacent normal tissues showed that TM4SF1 was highly expressed on tumor cell membranes, but not detected on normal cells
.
The researchers then examined the relationship between
TM4SF1 and CSCs.
They found that the MDA-MB-231 human breast cancer cells with TM4SF1 high had more CD44^high/CD24 low (known CSC markers) cells than in TM4SF1^low MDA-MB-231 cells.

MDA-MB-231 cells with TM4SF1^high and H460 human lung cancer cells formed more tumor spheroids after serial passage than the corresponding TM4SF1^low cells
.

Similar results have been demonstrated in various human cancer cell lines, including breast cancer cell lines (lung metastatic MDA-MB-231 and MDA-MB-453), melanoma cell lines (A375 and A2058), and lung cancer cell lines (H2030 and H1975).

In addition, pluripotency factors are upregulated
in TM4SF1^high cells of various human cancer cell lines.
These results indicate that TM4SF1 is a cell membrane marker for CSCs
.

In addition, the researchers used sequence-restricted dilution transplantation assays to determine the frequency of
tumor-initiating cells (T-IC).
Compared to TM4SF1^low MDA-MB-231 cells, TM4SF1^highMDA-MB-231 cells injected into mice exhibited faster tumor growth, higher T-IC frequency, and shorter latency
.
It is worth noting that TM4SF1 expression remained unchanged in the primary tumor formed by TM4SF1 high cells or TM4SF1^low cells, indicating that CSCs stably maintained^high expression
of TM4SF1.
Moreover, in the primary tumor formed by MDA-MB-231 cells with TM4SF1 high, the expression of CD44^high/CD24 low, CD133, NANOG, POU5F1 and SOX2 is higher than that of MDA-MB-231 cells formed by TM4SF1 ^low.
The results showed that the high expression of TM4SF1 maintained the CSC trait
stably.

To test whether the stem cells of TM4SF1^high cells can be stably passed on to offspring, the researchers conducted secondary and third transplant trials
.
Compared to TM4SF1^low cells, TM4SF1^high cell tumors grow faster, have higher T-IC frequency, and have a shorter
latency period.
In addition, fluorescence-activated cell sorting (FACS) analysis showed that TM4SF1 expression was maintained
in secondary and tertiary tumors formed by TM4SF1^high cells and TM4SF1^low cells, respectively.
These results suggest that TM4SF1^high cells have CSC properties, which are stably maintained and passed on to future generations
.

Since CSCs are also responsible for metastasis, the researchers examined whether TM4SF1 expression affected metastasis
.
Interestingly, more metastasis occurred in the lungs of mice injected with MDA-MB-231 cells injected with TM4SF1^high in situ, while multi-organ metastasis was promoted and survival time was shortened in mice injected
with MDA-MB-231 cells injected with TM4SF1^high intracardiographically.
Similar results
were obtained in A2058 and H2030 cells.
These results suggest that TM4SF1^high cells have a higher transfer capacity
than TM4SF1^low cells.

To examine whether TM4SF1 high cells require high TM4SF1 expression to possess and maintain CSC function, the researchers silenced TM4SF1 in TM4SF1^high MDA-MB-231 cells and found reduced
ball formation, tumor growth, T-IC frequency, and metastasis.
In addition, TM4SF1 deletion prolongs latency and survival time
after in situ injection.
In general, high TM4SF1 expression is a necessary and sufficient condition for
having and maintaining CSC characteristics.
Therefore, TM4SF1 may be a therapeutic target for the specific elimination of CSCs
.

Summary of the study